Clomid, generically known as clomiphene citrate, is often a first line drug to help induce ovulation in women. It is also commonly prescribed to men to treat infertility and low T. This article summarizes what Clomid is, how it works and when it is most likely to be effective as a fertility treatment for men.

What is Clomid?

Clomid has been around for a long time. It was first synthesized in 1956 and introduced into clinical medicine in 1968. It is part of a class of drugs called selective estrogen receptive modulators (SERMs) which mess with the way estrogen is used by the body. These kinds of drugs are used in women for birth control, a treatment for breast cancer, vaginal atrophy, osteoporosis and ovulation disorders. While formally approved only for conditions that affect women, SERMs have also been used “off-label” to counteract hormone imbalances in men as the drugs have been shown useful in combatting low T, gynecomastia and infertility.

(Note: “off-label” just means that regulatory authorities – e.g. the FDA in the U.S. – has not formally approved the drug for use in men. However, doctors can still prescribe the medication based on the clinical evidence that does exist. Think of it like using a screwdriver to open a paint can – it’s not called a “paint can opener”, but still does the job.)

How does Clomid work?

Clomid works by blocking estrogen receptors in the brain, which can increase the production of testosterone and sperm for men. Your body has a complex system for controlling its natural production of testosterone. The pituitary gland works a bit like a thermostat. When estrogen levels are low, it turns on and starts producing luteinizing hormone (LH) and follicle stimulating hormone (FSH). As estrogen levels increase, the pituitary gland shuts down. Clomid blocks the estrogen receptors in the brain and tricks it into thinking estrogen levels are low. In response, the pituitary gland continues to produce LH and FSH.

Luteinizing hormone produced by the pituitary gland stimulates Leydig cells in the testicle to begin producing testosterone. Most testosterone remains in the testicle where it supports the production and maturation of sperm. Excess testosterone leaks into the blood stream where most of it binds with sex-hormone binding globulin. A small fraction of the testosterone remains free (or bioavailable) and circulates through the body where it binds with various types of cells causing them to express proteins that are associated with masculine sex traits such as larger muscles, deeper voice, body hair, etc. A small portion of free testosterone is converted to estrogen by an enzyme called aromatase. Estrogen travels to the brain and binds to receptors in the pituitary gland causing it to stop producing luteinizing hormone. The drop in LH lowers production of testosterone in the testicle, which in turn lowers the amount of estrogen in the blood. Eventually, the pituitary gland fires back up and starts producing more LH starting the cycle again.

When Clomid is used to block estrogen receptors in the brain, the pituitary responds by generating greater amounts of LH and FSH. Higher levels of these hormones can push the testicle into over-drive – raising levels of sperm and natural testosterone.

Using Clomid to treat low testosterone

Clomid can be used to boost testosterone in men with low T and lower LH / FSH levels. Unlike Testosterone Replacement Therapy (TRT), Clomid rarely has a negative impact on fertility. TRT delivers synthetic testosterone directly into the blood stream. Some of the synthetic testosterone is converted into estrogen, causing the pituitary gland to shut down production of luteinizing hormone (LH). This in turn causes the testicle to shut down and can lead to permanent dependence on the external testosterone. Since Clomid helps your body produce natural testosterone, it can also be used in conjunction with TRT to maintain testicular function while receiving the external testosterone. Using Clomid can lower the dose of external testosterone needed to alleviate symptoms and / or protect fertility during TRT treatment.

Clomid is less effective as a treatment for low T in cases of testicular failure. Certain congenital defects, illnesses or injuries can damage tissues in the testicle and limit its ability to produce testosterone. If the testicle is having a hard time producing testosterone, the brain generally responds by naturally raising LH levels. Taking Clomid to further elevate LH is relatively ineffective. However, it can be helpful to use in conjunction with testosterone therapy to preserve fertility.

Using Clomid to treat male infertility

Clomid is most effective in treating infertility in men with lower testosterone levels and low to normal LH / FSH levels. It has also been somewhat effective in treating idiopathic oligospermia (low sperm count that doesn’t really have a clear cause). Follicle stimulating hormone (FSH) produced by the pituitary stimulates the division of sperm cells. Raising FSH levels can lead to higher sperm production.
Like we said, Clomid is “off-label” treatment for men. However, there are quite a few studies that document its effective use in men. Studies where Clomid was used as a treatment for low sperm count (oligospermia) often showed modest improvement in both count and motility and increased rate of pregnancy.

Clomid has also been studied as a treatment for non-obstructive azoospermia with pretty good results. After using clomiphene, 64.3% of the patients had sperm present in their semen analysis. The counts ranged from 1 to 16 million sperm/mL, with an average concentration of 3.8 million/mL. The 37.5% that remained azoospermic underwent testicular extraction of sperm and were able to have sperm retrieval sufficient for ICSI. This study was limited to 42 men, but it does suggest that Clomid can be effective as a treatment option in some cases of azoospermia.

Some side effects that have been observed include facial flushing, excessive sweating, gynecomastia and breast tenderness, weight gain, hypertension, cataracts, and acne. There is also a limited sub-set of men who seem to have a negative impact on semen quality when taking Clomid, so it is important to monitor the impact with occasional semen analysis.

Next generation of Clomid under development

Repros Therapeutics has developed a slightly altered version of Clomid specifically aimed as a therapeutic for men. The new formulation, called Androxal, is under clinical trials to become an FDA approved treatment for hypogonadism (low T). Past studies for the drug have examined testosterone, luteinizing hormone, follicle stimulating hormone and sperm count in men receiving different dosages of the drug and reporting any side effects experienced by patients. The data has come back with good results but is under heightened scrutiny by the FDA due to advertising practices and over-prescriptions of testosterone therapy.

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